chrX-45076679-CTTT-C

Variant names:

• chrX-45076679-CTTT-C
• rs10605935
• NM_001291415.2:c.2859-7_2859-5delTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):​c.2859-7_2859-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 805,245 control chromosomes in the GnomAD database, including 2 homozygotes. There are 23 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 2 hem., cov: 0)
  • Exomes 𝑓: 0.0020 (2 hom. 21 hem.)
• Consequence: KDM6A NM_001291415.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.198
• Publications: 5 publications found

Genes affected

KDM6A (HGNC:12637): (lysine demethylase 6A) This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

KDM6A Gene-Disease associations (from GenCC):

• Kabuki syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-45076679-CTTT-C is Benign according to our data. Variant chrX-45076679-CTTT-C is described in ClinVar as Benign. ClinVar VariationId is 194885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000158 (14/88378) while in subpopulation EAS AF = 0.00208 (6/2888). AF 95% confidence interval is 0.000904. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 14 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291415.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.2859-7_2859-5delTTT		splice_region intron	N/A	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2859-7_2859-5delTTT		splice_region intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.2757-7_2757-5delTTT		splice_region intron	N/A	NP_001406739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.2859-7_2859-5delTTT		splice_region intron	N/A	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2724-7_2724-5delTTT		splice_region intron	N/A	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2703-7_2703-5delTTT		splice_region intron	N/A	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 14 AN: 88373 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00207

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000793

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000667

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00386 AC: 306 AN: 79362 AF XY: 0.000716

Gnomad AFR exome AF: 0.000781

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0140

Gnomad FIN exome AF: 0.00306

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00198 AC: 1417 AN: 716867 Hom.: 2 AF XY: 0.000105 AC XY: 21 AN XY: 199911

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00123 AC: 24 AN: 19468

American (AMR) AF: 0.00115 AC: 29 AN: 25270

Ashkenazi Jewish (ASJ) AF: 0.00110 AC: 15 AN: 13697

East Asian (EAS) AF: 0.00866 AC: 199 AN: 22991

South Asian (SAS) AF: 0.00262 AC: 97 AN: 37036

European-Finnish (FIN) AF: 0.00211 AC: 67 AN: 31680

Middle Eastern (MID) AF: 0.00135 AC: 4 AN: 2971

European-Non Finnish (NFE) AF: 0.00169 AC: 902 AN: 532448

Other (OTH) AF: 0.00256 AC: 80 AN: 31306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000158 AC: 14 AN: 88378 Hom.: 0 Cov.: 0 AF XY: 0.000119 AC XY: 2 AN XY: 16796

African (AFR) AF: 0.000122 AC: 3 AN: 24636

American (AMR) AF: 0.00 AC: 0 AN: 7514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2258

East Asian (EAS) AF: 0.00208 AC: 6 AN: 2888

South Asian (SAS) AF: 0.00 AC: 0 AN: 1672

European-Finnish (FIN) AF: 0.000793 AC: 2 AN: 2523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 175

European-Non Finnish (NFE) AF: 0.0000667 AC: 3 AN: 44985

Other (OTH) AF: 0.00 AC: 0 AN: 1156

Alfa AF: 0.0111 Hom.: 1920

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Kabuki syndrome 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10605935; hg19: chrX-44935924;